tbuckley/cabot-search huggingface dataset:
Screening for Impaired Visual Acuity in Older Adults
Authors: Jill Jin
Journal: JAMA (2022)

US Preventive Services Task Force; Carol M. Mangione, MD, MSPH; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Cabana, MD, MA, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; John W. Epling Jr, MD, MSEd; Carlos Roberto Jaén, MD, PhD, MS; Alex H. Krist, MD, MPH; Martha Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Lori Pbert, PhD; John M. Ruiz, PhD; Melissa A. Simon, MD, MPH; James Stevermer, MD, MSPH; John B. Wong, MD
SHR-1701, a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, for Recurrent or Metastatic Cervical Cancer: A Clinical Expansion Cohort of a Phase I Study
Authors: Jifeng Feng, Dihong Tang, Jing Wang, Qi Zhou, Jin Peng, Hanmei Lou, Yuping Sun, Yunlang Cai, Hongmin Chen, Junqin Yang, Pan Liu, Linna Wang, Jianjun Zou
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Patients with recurrent or metastatic cervical cancer have limited treatment options after platinum-containing treatment. We initiated a phase I study to assess SHR-1701, a novel bifunctional fusion protein composed of a mAb against programmed death ligand 1 (PD-L1) fused with the extracellular domain of TGFβ receptor II, in solid tumors (NCT03774979). Here, results from the cervical cancer cohort are presented. Patients and Methods: Patients with recurrent or metastatic cervical cancer who progressed during or after platinum-based therapy were enrolled to receive SHR-1701 at 30 mg/kg every 3 weeks. Primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In total, 32 patients were recruited. ORR was 15.6% [95% confidence interval (CI), 5.3–32.8], and disease control rate was 50.0% (95% CI, 31.9–68.1). Responses were still ongoing in 80.0% of the responders; 6-month duration of response rate was 80.0% (95% CI, 20.4–96.9). Median progression-free survival (PFS) was 2.7 months (95% CI, 1.4–4.1). Of note, as assessed by immune-modified RECIST, median PFS was 4.1 months (95% CI, 1.6–4.3). Overall survival rate at 12 months was 54.6% (95% CI, 31.8–72.7). Treatment-related adverse events of grade 3 or 4 were reported in 11 (34.4%) patients. No treatment-related deaths occurred. No difference in ORR was found between patients with PD-L1 combined positive score ≥1 or &amp;lt;1; patients with high phosphorylated SMAD2 level in immune cells or tumor cells had numerically higher ORR. Conclusions: SHR-1701 exhibits encouraging antitumor activity and controllable safety in patients with recurrent or metastatic cervical cancer after platinum-based regimens, and therefore might provide another treatment option for this population. See related commentary by Miller and Friedman, p. 5238
Abstract 5993: Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1
Authors: Zhuo Zhang, Jingxia Li, Huailu Tu, Max Costa
Journal: Cancer Research (2022)

Abstract Bladder cancer is the fourth most common cancer in men in the United States. It has been reported that about 83,730 new cases of bladder cancer and 17,200 deaths from bladder cancer occurred in 2021. Therefore, the discovery of new alternative medication becomes extremely important for reduction of cancer mortality. Isorhapontigenin (ISO), a phytopolyphenol, is derivative stilbene isolated from the Chinese herb Gnetum cleistostachyum. It has been reported that ISO exhibits multiple anticancer activities in human high grade invasive bladder cancer cells. Our previous study has demonstrated that ISO treatment increased methyltransferase 14, N6-adenosine-methyltransferase subunit (METTL14), subsequently decreased vimentin, a key member of epithelial mesenchymal transition (EMT), resulting in reduced invasion of bladder cancer T24T cells. Autophagy maintains normal cell homeostasis through the removal of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Tumor-promoting or tumor-inhibiting functions of autophagy depends on the cancer type and stage. Sestrin 2, a member of stress-inducible protein family which is essential for maintaining metabolic homeostasis, is involved in the autophagy initiation. Beclin 1, a key autophagy regulator, is involved in multiple stages of autophagy. The present study investigated the mechanisms of ISO-inhibited migration and invasion in bladder cancer cells by focusing on Sestrin 2 and Beclin 1 pathways. Our results showed that ISO treatment in bladder cancer T24T decreased both migration and invasion as assessed by using transwell assays. However, in T24T cells with Sestrin 2 knockdown or Beclin 1 knockdown ISO lost the inhibitory effect on migration and invasion. The results from immunoblotting analysis showed that knockdown of Sestrin 2 or Beclin 1 increased N-cadherin and vimentin, two important members of EMT. While treatment with ISO in T24T wildtype cells decreased N-cadherin and vimentin, ISO did not have any effect on N-cadherin or vimentin in T24T cells with Sestrin 2 or Beclin 1 knockdown. Furthermore, ISO treatment reduced protein levels of Atg7 and Bcl-2 in T24T wildtype cells. ISO failed to decrease Atg7 and Bcl-2 in those T24T cells with Sestrin 2 or Beclin 1 knockdown. The present study suggested that ISO inhibits migration and invasion of bladder cancer cells and the inhibition of ISO is dependent on Sestrin 2 and Beclin 1, and induction of autophagy by ISO reduces migration and invasion of bladder cancer cells. The present study provides evidence that ISO can be a candidate of chemotherapy. Citation Format: Zhuo Zhang, Jingxia Li, Huailu Tu, Max Costa. Inhibition of isorhapontigenin on migration and invasion of bladder cancer cells depends on Sestrin 2 and Beclin 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5993.
Abstract 3154: Assessing hematopoietic stem cell fitness within a nanobioreactor in microgravity
Authors: Luisa Ladel, Jessica Pham, Isabelle Oliver, Larisa Balaian, Catriona HM Jamieson
Journal: Cancer Research (2022)

Abstract Microgravity coupled with increased radiation exposure aboard the ISS provides a unique environment to simulate and study response to injury, inflammatory signaling, aging, and (pre-)malignant transformation of normal human hematopoietic stem cells (HSCs) in an accelerated timeframe. The NASA Twins study suggests that genomic, epigenomic, epitranscriptomic, and proteomic changes may detrimentally impact hematopoietic stem and immune cell fitness and induce stem cell exhaustion (Garrett-Bakelman et al., Science, 2019). Moreover, changes indicative of pre-cancer stem cell generation such as increased chromosome translocations and inversions occurred and persisted post-flight. Additionally, a recent publication entitled Multisystem Toxicity in Cancer: Lessons from NASA’s Countermeasures Program found significant similarities between the multisystem physiological toxicities in cancer patients and during spaceflight (Scott et al, Cell 2019). These reports highlight the benefits of studying injury response, changes in mutational profiles and cancer evolution in microgravity at the stem cell level. For this study, we designed a novel bioreactor system to support the culture of donor-derived human HSCs in low Earth orbit (LEO). A sponge matrix and stromal cells model the microenvironment HSCs reside in within the bone marrow niche. Testing on Earth confirmed our system’s ability to maintain stem cell fitness over several weeks. To assess stem cell physiology in LEO over time, we lentivirally transduce a reporter into the HSCs pre-flight (Pineda et al., Scientific Reports 2016), which allows for cell cycle tracking via fluorescence imaging. This will provide data for assessment of stem cell health, maintenance and functionality. Furthermore, we will be analyzing mutational status post-flight, with a focus on signatures we have previously connected to (pre-)malignant transformation via RNA sequencing analysis (Jiang, Cancer Cell 2019). Our bioreactors are scheduled to launch as part of the SpaceX CRS-24 mission on Dec 21, 2021. This investigation may provide valuable insights into the maintenance of hematopoietic stem cell health and functionality, response to injury through accumulation of mutations and, eventually, the mechanisms fueling long-term (pre-)malignant transformation into leukemia stem cells. Citation Format: Luisa Ladel, Jessica Pham, Isabelle Oliver, Larisa Balaian, Catriona HM Jamieson. Assessing hematopoietic stem cell fitness within a nanobioreactor in microgravity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3154.
Abstract 165: Characterizing CLK3 in the colonic epithelium
Authors: Carly Cabel, Curtis Thorne
Journal: Cancer Research (2022)

Abstract The purpose of this study is to determine the function of CLK3 in the colonic epithelium and colon cancer. The intestinal epithelium undergoes constant renewal and is tightly regulated. Disruption of its homeostasis can result in the development of colorectal cancer (CRC). Glycogen synthase kinase 3 (GSK3) is a kinase that plays a central role in multiple signaling pathways including cellular proliferation. Our lab previously performed an siRNA screen to investigate hundreds of kinases to identify candidates which could interact with GSK3. Among the over 500 kinases that were tested, a protein kinase called CDC-like kinase 3 (CLK3) was identified as the strongest interaction with GSK3. We found that inhibition of GSK3 and CLK3 synergized to kill cancer cells. This led us to focus on CLK3 as a potential therapeutic target kinase in colon cancer. CLK3 is part of a four-member family of CDC-like kinases involved in pre-mRNA splicing. They are dual-specificity kinases, meaning they can target both tyrosine and serine/threonine substrates. CLK3 is also a poor prognostic marker in colon cancer, with high expression of CLK3 leading to poor outcome of disease. In human colonic epithelial cells, we show that loss of CLK3 dampens Wnt response. This data, along with the strong genetic interaction with GSK3, suggests a role of CLK3 in the Wnt pathway. Because Wnt signaling is higher in the stem cell region of the crypt, and CLK3 shows a role in Wnt activity in human colonic epithelial cells, we hypothesize that CLK3 regulates mRNA splicing to promote Wnt signaling and stemness in colonic progenitor cells and carcinogenesis. We are currently performing transcriptomics and phosphoproteomics in CLK3 CRISPR knockout cells to identify an mRNA-splicing and phosphorylation signature. We have found that the induction of Wnt-related pathway genes are lost in CLK3 knockout cells. Additionally, we are categorizing CLK3-dependent pre-mRNAs splicing events into functional groups controlling cell fate and validating in patient-derived normal and tumor organoid models. This work highlights CLK3 as a critical regulator of gut stem cells and potentially colorectal cancer stem cells. Citation Format: Carly Cabel, Curtis Thorne. Characterizing CLK3 in the colonic epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 165.
Abstract 3573: DNA immunotherapy targeting BARF1 demonstrates therapeutic impact in novel murine carcinoma models expressing EBV latent antigens
Authors: Xizhou Zhu, Alfredo Perales-Puchalt, Krzysztof Wojtak, Ziyang Xu, Kun Yun, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Daniel H. Park, Kevin Liaw, Mamadou A. Bah, Paul M. Lieberman, Ebony N. Gary, Ami Patel, David B. Weiner
Journal: Cancer Research (2022)

Abstract Epstein Barr Virus (EBV) latent infection is associated with multiple types of cancer. Several clinical studies have targeted EBV antigens as immune therapeutic targets with limited efficacy of EBV+ malignancies, suggesting additional targets might be important. BamHI-A rightward frame 1 (BARF1) is an EBV antigen that is highly expressed in EBV-associated gastric carcinoma (EBVaGC) and EBV+ nasopharyngeal carcinoma (NPC) and has not been evaluated as an antigen in the context of therapeutic immunization. Here, we developed a synthetic DNA-based expression cassette as immunotherapy targeting BARF1 (pBARF1). Immunization with pBARF1 induced potent antigen-specific humoral and polyfunctional effector T cell responses in vivo. We observed significant antigen-specific increases of IFN-γ+, IFN-γ+ TNF-α+, and IFN-γ+ TNF-α+ IL-2+ populations in CD8+ T cells from the pBARF1 immunized animals in both C57BL/6 and BALB/c mice. Novel BARF1 expressing carcinoma lines that grow in immune-competent animals were developed as surrogates for human EBV+ tumors. We confirmed that BARF1 expression in these new cancer cell lines, MC38-BARF1 and CT26-BARF1, was within the range of human EBV+ cancer cell lines, SNU719 and C666-1. Immunization with pBARF1 plasmid demonstrated impact of tumor progression through induction of CD8+ T cell in these BARF1+ carcinoma models. We also observed long-term antitumor immunity, at least up to 446 days, against BARF1 in a CT26-BARF1 rechallenge study. Using IVIS in vivo imaging, we observed that pBARF1 immunized animals rapidly controlled and cleared cancer cells. These studies demonstrate the potential for pBARF1 immunity to induce antigen-specific immune responses impacting tumor progression. Further study of this immune target and these EBV+ tumor models is likely important as part of therapeutic approaches for EBV+ malignancies. Citation Format: Xizhou Zhu, Alfredo Perales-Puchalt, Krzysztof Wojtak, Ziyang Xu, Kun Yun, Pratik S. Bhojnagarwala, Devivasha Bordoloi, Daniel H. Park, Kevin Liaw, Mamadou A. Bah, Paul M. Lieberman, Ebony N. Gary, Ami Patel, David B. Weiner. DNA immunotherapy targeting BARF1 demonstrates therapeutic impact in novel murine carcinoma models expressing EBV latent antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3573.
Abstract 5935: Malignant risk assessment of clinical and histological subtypes of lichenoid mucositis with dysplasia
Authors: Iris Lin, Oh Run Kim, Leigha Rock, Lewei Zhang, Miriam Rosin, Martial Guillaud, Denise Laronde
Journal: Cancer Research (2022)

Abstract Introduction: Oral lichen planus (OLP), a common, chronic inflammatory condition, is categorized as potentially malignant by the World Health Organization. However, some hypothesize that only lichenoid lesions with dysplasia (LLD) are at risk of progression to cancer. Others have proposed subtypes of LLD, with differing malignant risks. Objectives: To determine if subtypes of LLD exist, based on clinical and histological features, and to determine the proportion of malignant progression in these subtypes. Methods: A nested case control study was conducted using tissue samples and longitudinal data of patients enrolled in the Oral Cancer Prediction Longitudinal study. Inclusion criteria were a biopsy confirmed diagnosis of lichenoid mucositis with dysplasia, no history of head and neck cancer, at least 5 years of follow-up, and accessible clinical photographs and bio-banked tissue. A chart review was conducted, and photographs reviewed to assess for lesion features characteristic of OLP. Histological sections were examined for lichenoid inflammation, and immunohistochemical staining for collagen IV was used to evaluate the integrity of the basement membrane (BM). Two subtypes of LLD were proposed: 1) a primary lichenoid and secondary dysplastic (L1D2) type defined as a lesion with a reticular and bilateral clinical presentation, subepithelial inflammation, and evidence of BM degeneration, and 2) a primary dysplastic and secondary lichenoid type (D1L2), which may present unilaterally or bilaterally, clinically resemble OLP or leukoplakia, and exhibit subepithelial inflammation with or without evidence of BM degeneration. Association with outcome, which was defined as progression to severe dysplasia, carcinoma in situ, or squamous cell carcinoma, was tested using Fisher’s Exact test. Results: All progressing cases had a non-homogenous clinical presentation (P=0.005) and were more apt to change (in size, texture, and/or appearance) over time (P=0.002). A reticular, smooth appearance was more common in non-progressing cases (P=0.007, P=0.016, respectively). 30% of cases in the D1L2 subtype progressed to malignancy, compared to none in the L1D2 group, though this finding did not reach statistical significance (P=0.081). Conclusion: LLD with a non-homogenous, non-reticular clinical presentation are at greater risk of progression, and a high proportion of cases exhibiting primary dysplastic features progressed to malignancy, indicating that LLD should be under close clinical follow-up. Citation Format: Iris Lin, Oh Run Kim, Leigha Rock, Lewei Zhang, Miriam Rosin, Martial Guillaud, Denise Laronde. Malignant risk assessment of clinical and histological subtypes of lichenoid mucositis with dysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5935.
Abstract 2855: Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia
Authors: Yan Luo, Kaihin Lui, Tommy T. To, Andrew liu, Farah Yassine, Mohamed A. Kharfan Dabaja, Martha E. Gadd, Hong Qin
Journal: Cancer Research (2022)

Abstract B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults with CD19-targeting CAR T-cell therapy showing an excellent initial curative response. However, 10-20% of patients who receive anti-C19 CAR T-cell treatment experience relapse due to CD19 antigen loss. B-cell activating factor receptor (BAFF-R) that is expressed on the surface of normal and neoplastic B cells mediates the survival of mature peripheral B cells along with the B-cell receptor. Since B-CLL is characterized by apoptotic disruption and subsequent accumulation of mature B cells, BAFF-R is a logical, novel target for CAR T-cell therapy directed against B-CLL, especially if CD19 antigen loss occurs. In this study, we first manufactured BAFF-R CAR T-cells by infecting healthy donor Tnaïve/memory (Tn/mem) cells with BAFF-R CAR lentivirus before evaluating the antitumor activity of BAFF-R CAR T-cells on wild type MEC-1 (a B-CLL cell line), modified MEC-1, and primary cell lines. Antigen-specific cytotoxicity and activation of the BAFF-R CAR T-cells or control CD19 CAR T-cells were determined upon incubation with B-CLL cell lines and patient-derived primary B-CLL by measuring degranulation and IFN-γ release, respectively. BAFF-R CAR T-cells demonstrated substantial cytotoxicity against MEC-1, CD19-deficient MEC-1, and primary B-CLL cell lines; CD19 CAR T-cells showed no effect on CD19-deficient MEC-1 cells but did show effects with primary B-CLL and MEC-1 cells. Similarly, the release of IFN-γ was greater when BAFF-R CAR T-cells were co-cultured with CD19-deficient MEC-1 or primary B-CLL compared to CD19 CAR T-cells co-cultured with CD19-deficient MEC-1. In summary, BAFF-R CAR T-cells exert significant antitumor properties not only on patient-derived primary B-CLL cells but also on a CD19-deficient B-CLL cell line. We, therefore, assert BAFF-R-targeting CAR T-cells to be a novel therapeutic avenue for patients newly diagnosed with B-CLL and patients experiencing relapsed B-CLL after anti-CD19 therapy. Citation Format: Yan Luo, Kaihin Lui, Tommy T. To, Andrew liu, Farah Yassine, Mohamed A. Kharfan Dabaja, Martha E. Gadd, Hong Qin. Antitumor activity of BAFF-R targeting CAR T-cells on chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2855.
Dietary Selenium Across Species
Authors: Xin Gen Lei, Gerald F. Combs, Roger A. Sunde, Joel S. Caton, John D. Arthington, Marko Z. Vatamaniuk
Journal: Annual Review of Nutrition (2022)

This review traces the discoveries that led to the recognition of selenium (Se) as an essential nutrient and discusses Se-responsive diseases in animals and humans in the context of current understanding of the molecular mechanisms of their pathogeneses. The article includes a comprehensive analysis of dietary sources, nutritional utilization, metabolic functions, and dietary requirements of Se across various species. We also compare the function and regulation of selenogenomes and selenoproteomes among rodents, food animals, and humans. The review addresses the metabolic impacts of high dietary Se intakes in different species and recent revelations of Se metabolites, means of increasing Se status, and the recycling of Se in food systems and ecosystems. Finally, research needs are identified for supporting basic science and practical applications of dietary Se in food, nutrition, and health across species.
Abstract 1803: Lethal synthesis: Potent anticancer activity of a glycine uptake inhibitor in tumor cells with mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) knocked down
Authors: Gulam Mohmad Rather, Joseph R. Bertino
Journal: Cancer Research (2022)

Abstract Methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme with dehydrogenase and cyclohydrolase activity. MTHFD2 is expressed in embryonic tissues and not in adult tissues, and by generating formate for purine biosynthesis, enhances proliferation. It is over expressed in many cancers, including breast cancer, and has become an important cancer drug target. Knockdown (KD) of MTHFD2 in breast cancer cell lines MCF7 and T47D, slowed proliferation and resulted in an increase in early apoptosis and a S-phase block. Lack of MTHFD2 causes a dependence on glycine, and in the absence of glycine, proliferation of the MCF-7 cell line with MTHFD2 knocked down was inhibited even further. A known specific glycine transporter type-I (GlyT1) inhibitor, ORG 25935 potently inhibited growth of MCF7 cell with MTHFD2 KD, while it had less of an effect on T47D cells with MTHFD2 KD. Furthermore, both cell lines with MTHFD2 KD showed increase in expression of GlyT1 (SLC6A9) at both mRNA and protein level, using the qPCR and western blotting, respectively. The metabolomics studies showed that intracellular glycine, and NAD+ pools are more reduced in control cells compared to MTHFD2 KD cells on treatment with GlyT1 inhibitor, suggesting that this inhibitor causes glycine depletion in the cells. These data encourage the development of inhibitors of MTHFD2 for use in combination with glycine transport inhibitors. Citation Format: Gulam Mohmad Rather, Joseph R. Bertino. Lethal synthesis: Potent anticancer activity of a glycine uptake inhibitor in tumor cells with mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) knocked down [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1803.